Total synthesis of lithospermic acid using Fe-catalyzed Cross-Dehydrogenative-Coupling reaction and Pd-catalyzed ester-directed CH olefination

Tetrahedron 74 (2018) 5950e5954

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Tetrahedron journal homepage: www.elsevier.com/locate/tet

Total synthesis of lithospermic acid using Fe-catalyzed Cross-Dehydrogenative-Coupling reaction and Pd-catalyzed ester-directed CeH olefination Yong Zheng, Weibin Song, Yefu Zhu, Bole Wei, Lijiang Xuan* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 17 June 2018 Received in revised form 14 August 2018 Accepted 20 August 2018 Available online 23 August 2018

The total synthesis of lithospermic acid has been accomplished employing two CeH activation reactions as key steps. Fe-catalyzed Cross-Dehydrogenative-Coupling reaction was used for the rapid construction of benzofuran framework. Pd-catalyzed ester-directed CeH olefination allowed the efficient assembly of the dihydrobenzofuran ester and acrylate moieties. © 2018 Elsevier Ltd. All rights reserved.

Keywords: Total synthesis Lithospermic acid Cross-Dehydrogenative-Coupling CeH olefination

1. Introduction Lithospermic acid (Fig. 1) is originally isolated from Lithospermum ruderale in 1963, and its gross structure was fully elucidated in 1975 [1,2]. It is one of the pharmaceutically active components of traditional Chinese medical plant Danshen (Salvia miltiorrhiza), which is used for the treatment of cardiovascular and cerebrovascular diseases [3]. Recently, lithospermic acid has been shown to exhibit HIV-1 integrase inhibition activity (IC50 ¼ 1.4 mM) [4]. Owing to its remarkable biological profiles, limited availability from natural sources, and intriguing structural features, total synthesis of lithospermic acid have spurred considerable interest of the synthetic community. In 2005, Ellman and Bergman group reported the first total synthesis of (þ)-lithospermic acid by exploiting Rhcatalyzed asymmetric intramolecular CeH alkylation as a key step [5]. Yu group also achieved total synthesis of lithospermic acid via Rh-catalyzed carbene CeH insertion and a late-stage Pd-catalyzed intermolecular CeH olefination [6]. Since then, Coster, Ghosh and Hyu groups have completed their total synthesis respectively [7e9]. It is still highly desirable to develop a concise synthetic route

* Corresponding author. E-mail address: [email protected] (L. Xuan). https://doi.org/10.1016/j.tet.2018.08.028 0040-4020/© 2018 Elsevier Ltd. All rights reserved.

to lithospermic acid analogues for the evaluation of their potentials as lead compounds in drug research. Recently, metal-catalyzed CeH activation has emerged as a powerful and economical tool for the total synthesis of natural products, owing to its remarkable potential for step and atom economy [10]. Our group has recently accomplished the first total synthesis of salvianoic acid A by employing Ru-catalyzed CeH olefination as a key step [11]. As part of our interest to explore synthesis and structural modification of bioactive compounds from Salvia miltiorrhiza, we herein report a concise total synthesis of lithospermic acid using two CeH activation reactions as key steps. Fe-catalyzed Cross-Dehydrogenative-Coupling (CDC) was utilized for the rapid construction of benzofuran skeleton [12]. The dihydrobenzofuran ester and acrylate fragments were coupled by Pdcatalyzed ester-directed CeH olefination [13].

2. Results and discussion Our retrosynthetic analysis is depicted in Scheme 1. We envisioned that hepatmethyl lithospermic acid 2 could be assembled from dihydrobenzofuran ester 3 and acrylate subunit 4 by Pdcatalyzed ester-directed CeH olefination. Alcohol 5 was synthesized through metal-participated asymmetric reaction of 7 with the optically pure 2,3-epoxypropionate 6, which has been reported in

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Table 1 Optimization of Fe-catalyzed CDC reactiona.

Fig. 1. (þ)-Lithospermic acid (1). Entry

R

Catalyst

Oxidant

1 2 3 4 5 6 7 8 9 10

OMe OMe OMe OMe OMe OMe OMe OMe H Br

FeCl3$6H2O FeSO4 Fe(acac)3 FeCl3$6H2O FeCl3$6H2O FeCl3$6H2O FeCl3$6H2O FeCl3$6H2O FeCl3$6H2O FeCl3$6H2O

(t-BuO)2 (t-BuO)2 (t-BuO)2 t-BuOOH O2 O2 O2 O2 (t-BuO)2 (t-BuO)2

11

Br

FeCl3$6H2O

(t-BuO)2

Ligand

1,10-phenanthroline 2,20 -bipyridine pyridine

Yield (%)b 5 trace trace 0 20 35 19 10 72 55

1,10-phenanthroline

64

a

Reaction conditions: phenol (0.3 mmol), 10 (0.2 mmol), Fe catalyst (10 mol%), oxidant (0.3 mmol) or O2 (1 atm), ligand (20 mol %), DCE (2 mL), 100  C, 12 h. b Isolated yield.

Scheme 1. Retrosynthetic analysis of heptamethyl lithospermic acid (2).

Scheme 2. Synthesis of (±)-dihydrobenzofuran ester 3.

our previous work [11]. Dihydrobenzofuran ester 3 was prepared via MgeNH4Cl reduction of benzofuran ester 8. Construction of 8 could be achieved by Fe-catalyzed CDC reaction of phenol 9 with bketo ester 10. We initially began to synthesize benzofuran ester 8 from 2methoxylphenol 9 and b-keto ester 10 by Fe-catalyzed CDC reaction. Disappointedly, by using FeCl3$6H2O as catalyst and (t-BuO)2 as oxidant, the desired product 8 resulted in 5% yield (Table 1, entry 1). Other Fe catalysts and oxidants failed to afford the desired product (Table 1, entries 2e4). When oxygen was used as oxidant, 8 would be obtained in 20% yield (Table 1, entry 5). The yield was increased to 35% when 1,10-phenanthroline was added as ligand (Table 1, entry 6). Using other ligands, such as 2,20 -bipyridine and pyridine, did not further improve the yield (Table 1, entries 7 and 8). All attempts to synthesize 8 by CDC reaction in acceptable yield were in vain. We suspected that the unsatisfactory yield of 8 arose from the presence of ortho-methoxyl group in phenol 9. We then turned our attention to other 2-substituted phenols. Gratifyingly, the reaction between phenol 9a and b-keto ester 10 gave 8a in 72% yield (Table 1, entry 9). 2-bromophenol 9b, reacting with 10 under FeCl3 and (t-BuO)2 conditions, afforded the desired product 8b in 55% yield (Table 1, entry 10). The yield was improved to 64% by adding 1,10-phenanthroline as ligand (Table 1, entry 11). Having successfully prepared benzofuran ester 8b, we next examined the possibility of transforming 8b into 8 (Scheme 2). Fortunately, Ullman coupling of 8b with MeONa in the presence of CuBr proceeded smoothly to furnish the desired product in 78%

yield. Reduction of benzofuran ester 8 under Mg and NH4Cl in MeOH successfully gave the corresponding (±)-trans-dihydrobenzofuran ester 3 in 67% yield without affecting ester group. With (±)-dihydrobenzofuran ester 3 in hand, we next investigated Pd-catalyzed CeH olefination for coupling of (±)-dihydrobenzofuran ester 3 and acrylate 4. In Yu's previous work, carboxylic acid group was employed as directing group for a late stage CeH olefination to construct the lithospermic acid [6]. Inspired by examples of phenylacetic ester-directed CeH olefination, we envisioned that phenylacetic ester group in (±)-3 could be utilized as directing group for CeH olefination, which avoids preparing acid by hydrolysis of ester [13]. To test our hypothesis, dihydrobenzofuran ester 3 and methyl acrylate 11 were chosen as standard substrates to test the CeH olefination. To our delight, the coupling product 12 was obtained in 17% yield with Pd(OAc)2 and Ag2CO3 in HFIP (Table 2, entry 1). Further optimization of ligand revealed that the yield of 12 was improved to 81% when Ac-Gly-OH was used as the ligand (Table 2, entries 2e4). Other silver salts gave lower yields than Ag2CO3 for the CeH olefination (Table 2, entries 5e7). Having established the optimized conditions for Pd-catalyzed CeH olefination, we returned to the total synthesis of 1 (Scheme 3). CeH Olefination of (±)-trans-dihydrobenzofuran ester 3 with acrylate subunit 4 under the standard conditions to provide the desired coupling product 2 and its diastereomer 13. Single diastereomer 2 could be separated in 34% yield from the mixtures of 2 and 13 by preparative HPLC. Next, treatment of 2 with Me3SnOH in

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synthesis of lithospermic acid, which would facilitate further studies on the synthesis and biological evaluation of lithospermic acid analogues.

Table 2 Optimization of Pd-catalyzed ester-directed CeH olefinationa.

4. Experimental section 4.1. General information

Entry

Ag salt

ligand

Yield(%)b

1 2 3 4 5 6 7

Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 AgOAc Ag2O AgNO3

Ac-Gly-OH Ac-Ala-OH Ac-Leu-OH Ac-Gly-OH Ac-Gly-OH Ac-Gly-OH

17 81 68 54 46 43 61

a Reaction conditions: 3 (0.2 mmol), 11 (0.4 mmol), Pd(OAc)2 (5 mol%), Ag salt (0.4 mmol), ligand (20 mol%), HFIP (2 mL), air, 90  C, 48 h. b Isolated yield.

All the reagents were used without further purification. The solvents were dried by the standard methods. 1H and 13C NMR spectra were recorded on a Bruker NMR spectrometer with TMS as an internal standard. HRESIMS was measured on an Agilent G6224A TOF spectrometer. TLC was performed on pre-coated silica gel GF254 plates (Qingdao Marine Chemical Factory). Column chromatography was performed on silica gel (200e300 mesh, Qingdao Marine Chemical Factory). Visualization was carried out with UV or anisaldehyde staining. 4.2. Methyl 7-bromo-2-(3,4-dimethoxyphenyl)benzofuran-3carboxylate (8b) To a solution of 10 (4 mmol, 1.01 g) and 9b (6 mmol, 720 mg) in DCE (10 mL) was added FeCl3$6H2O (10 mol%, 108 mg), 1,10phenantroline (20 mol%, 144 mg) and (t-BuO)2 (8 mmol, 1.2 g) under N2. The mixture was stirred at 100  C for 12 h. The reaction mixture was cooled to room temperature and sat. NaHCO3 was added. The mixture was extracted by DCM for three times. The organic layers were combined, and dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to give 8b as white powder (998 mg, 64%). 1 H NMR (400 MHz, CDCl3) d 7.88 (dd, J ¼ 8.0, 1.1 Hz, 1H), 7.71e7.64 (m, 2H), 7.40 (dd, J ¼ 7.9, 1.1 Hz, 1H), 7.11 (t, J ¼ 7.9 Hz, 1H), 6.90 (d, J ¼ 8.3 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H). 13C NMR (100 MHz, CDCl3) d 164.3, 161.3, 151.2, 150.5, 148.5, 128.6, 128.0, 125.2, 123.3, 121.8, 121.5, 112.6, 110.6, 108.3, 103.7, 56.1, 56.0, 51.8. HRMS-ESI (m/z): calcd for C18H15BrNaO5 [M þ Na]þ 413.0001, found 413.0000. 4.3. Methyl 2-(3,4-dimethoxyphenyl)-7-methoxybenzofuran-3carboxylate (8)

Scheme 3. Total synthesis of lithospermic acid 1.

DCE provided diacid 14 in 85% yield [14]. Finally, subsequent removal of methyl groups in diacid 14 with TMSI-quinoline gave the natural product (þ)-lithospermic acid 1. 3. Conclusions In summary, we have accomplished the total synthesis of lithospermic acid starting from 2-bromophenol, involving two metalcatalyzed CeH activation reactions. Fe-catalyzed Cross-Dehydrogenative-Coupling was utilized for the rapid construction of dihydrobenzofuran ester fragment. The dihydrobenzofuran ester and acrylate fragments were coupled by Pd-catalyzed ester-directed CeH olefination. This work provides a concise method towards the

8b (0.5 mmol, 185 mg), CuBr (0.05 mmol, 12 mg), freshly prepared NaOMe (2 mmol, 216 mg), MeOH (1 mL), and anhydrous DMF (3 mL) were added into sealed tube under N2. The mixture was stirred at 130  C for 24 h. The reaction mixture was cooled to room temperature and sat. NH4Cl was added. The mixture was extracted by EtOAc for three times. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to give 8 as white powder (133 mg, 78%). 1 H NMR (400 MHz, CDCl3) d 7.75e7.72 (m, 2H), 7.64 (dt, J ¼ 7.9, 1.5 Hz, 1H), 7.28 (d, J ¼ 8.0 Hz, 1H), 6.99 (d, J ¼ 9.0 Hz, 1H), 6.88 (dd, J ¼ 8.0, 1.0 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 164.6, 161.0, 150.8, 148.4, 145.1, 142.9, 129.0, 124.6, 123.1, 122.0, 114.7, 112.5, 110.5, 108.1, 107.1, 56.1, 56.0, 56.0, 51.6. HRMS-ESI (m/z): calcd for C19H18NaO6 [M þ Na]þ 365.1001, found 365.1000. 4.4. (±)-Methyl 2-(3,4-dimethoxyphenyl)-7-methoxy-2,3dihydrobenzofuran-3-carboxylate (3) To a solution of 8 (1.2 mmol, 410 mg) in THF (15 mL) and MeOH (15 mL) was added freshly activated magnesium turning (3.6 mmol, 86 mg) and NH4Cl (2.4 mmol, 127 mg) under N2. The mixture was

Y. Zheng et al. / Tetrahedron 74 (2018) 5950e5954

stirred at 15  C for 5 h, and then stirred at room temperature for 24 h. Reaction was cooled to 15  C before sat. NH4Cl was added. The mixture was extracted by EtOAc for three times. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to give (±)-3 as yellow oil (276 mg, 67%). 1H NMR (400 MHz, CDCl3) d 7.10e6.72 (m, 6H), 6.08 (d, J ¼ 8.4 Hz, 1H), 4.36 (d, J ¼ 8.4 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H). 13C NMR (100 MHz, CDCl3) d 171.2, 149.2, 147.8, 144.6, 132.5, 125.1, 121.5, 118.8, 117.0, 112.5, 111.1, 109.3, 86.6, 56.1, 56.0, 56.0, 55.9, 52.7. HRMS-ESI (m/z): calcd for C19H20NaO6 [M þ Na]þ 367.1158, found 367.1156. 4.5. (R)-3-(3,4-dimethoxyphenyl)-1-methoxy-1-oxopropan-2-yl acrylate (4) To a solution of alcohol (2 mmol, 480 mg) and acrylic acid (3 mmol, 258 mg) in DCM (20 mL) was added DMAP (4 mmol, 488 mg) and EDCI (4 mmol, 764 mg) under N2. The reaction mixture was stirred at room temperature for 24 h. After completion of reaction, 1 N HCl was added at 0  C. The mixture was extracted by EtOAc for three times. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to give 4 as colorless oil (517 mg, 88%). 1 H NMR (400 MHz, CDCl3) d 6.75e6.81 (m, 3H), 6.45 (d, J ¼ 17.2 Hz, 1 H), 6.12e6.19 (m, 1H), 5.89 (d, J ¼ 10.4 Hz, 1 H), 5.26e5.29 (m, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H), 3.07e3.19 (m, 2H). 13C NMR (100 MHz, CDCl3) d 169.9, 165.1, 148.6, 147.9, 131.9, 128.1, 127.4, 121.3, 112.3, 111.1, 73.2, 55.8, 52.4, 37.1. HRMS-ESI (m/z): calcd for C15H18NaO6 [M þ Na]þ 317.1001, found 316.9997. 4.6. (±)-methyl 2-(3,4-dimethoxyphenyl)-7-methoxy-4-((E)-3methoxy-3-oxoprop-1-en-1-yl)-2,3-dihydrobenzofuran-3carboxylate (12) (±)-3 (0.2 mmol, 69 mg), methyl acrylate 11 (0.4 mmol, 35 mg), Ag2CO3 (0.4 mmol, 110 mg), Ac-Gly-OH (20 mol%, 10 mg), Pd(OAc)2 (5 mol%, 5 mg) and HFIP (2 mL) was added into sealed tube. The mixture was stirred at 90  C for 48 h. After the reaction was cooled to room temperature, the mixture was filtered by Celite and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to give 12 as colorless oil (70 mg, 81%). 1H NMR (500 MHz, CDCl3) d 7.70 (d, J ¼ 15.9 Hz, 1H), 7.21 (d, J ¼ 8.6 Hz, 1H), 6.91 (dd, J ¼ 7.8, 1.1 Hz, 1H), 6.89 (d, J ¼ 8.6 Hz, 1H), 6.88 (d, J ¼ 2.0 Hz, 1H), 6.83 (d, J ¼ 8.3 Hz, 1H), 6.29 (d, J ¼ 15.9 Hz, 1H), 6.04 (d, J ¼ 5.8 Hz, 1H), 4.49 (d, J ¼ 5.8 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H). 13C NMR (126 MHz, CDCl3) d 171.86, 167.41, 149.29, 149.23, 148.43, 146.19, 141.12, 132.29, 125.00, 124.52, 120.56, 118.08, 117.35, 112.94, 111.11, 108.73, 87.53, 56.18, 55.96, 52.89, 51.70. HRMS-ESI (m/z): calcd for C23H24NaO8 [M þ Na]þ 451.1363, found 451.1382. 4.7. (2S,3S)-methyl 2-(3,4-dimethoxyphenyl)-4-((E)-3-(((R)-3(3,4-dimethoxyphenyl)-1-methoxy-1-oxopropan-2-yl)oxy)-3oxoprop-1-en-1-yl)-7-methoxy-2,3-dihydrobenzofuran-3carboxylate (2) (±)-3 (0.2 mmol, 69 mg), 4 (0.4 mmol, 118 mg), Ag2CO3 (0.4 mmol, 110 mg), Ac-Gly-OH (20 mol%, 10 mg), Pd(OAc)2 (5 mol%, 5 mg) and HFIP (2 mL) was added into sealed tube. The mixture was stirred at 90  C for 48 h. After the reaction was cooled to room temperature, the mixture was filtered by celite and concentrated in

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vacuo. The resulting residue was subjected to HPLC (YMC Diol-NP column, 150 mm  20 mm, 5 mm particle size, 5:95 to 15:85 iPrOH:hexanes over 65 min at 9 mL/min, detection: UV at 254 nm) to afford 2 (43 mg, 34%). 1 H NMR (500 MHz, CDCl3) d 7.73 (d, J ¼ 15.9 Hz, 1H), 7.19 (d, J ¼ 8.5 Hz, 1H), 6.86e6.90 (m, 3H), 6.82 (d, J ¼ 8.5 Hz, 1H), 6.75e6.79 (m, 3H), 6.32 (d, J ¼ 16Hz, 1H), 6.02 (d, J ¼ 5.6 Hz, 1H), 5.31 (dd, J ¼ 8.5, 5.5 Hz, 1H), 4.45 (d, J ¼ 5.6 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.83 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.16 (dd, J ¼ 14.3, 4.7 Hz, 1H), 3.09 (dd, J ¼ 14.3, 8.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) d 171.80, 170.40, 166.21, 149.39, 149.32, 148.86, 148.55, 148.13, 146.49, 142.58, 132.39, 128.41, 125.07, 124.44, 121.53, 120.98, 118.13, 116.52, 112.98, 112.46, 111.20, 112.20, 108.81, 87.57, 73.19, 56.27, 56.04, 56.00, 56.00, 55.96, 55.92, 52.94, 52.47, 37.23. HRMS-ESI (m/z): calcd for C34H36NaO12 [M þ Na]þ 659.2099, found 659.2099. [a]23 D ¼ þ139 (c 0.39, CH2Cl2), lit. [a]D ¼ þ134.5 (c 0.49, CH2Cl2) [5], [a]25 D ¼ þ131.9 (c 0.079, CH2Cl2) [7]. Melting point: 58e59  C. 4.8. (2S,3S)-4-((E)-3-((R)-1-carboxy-2-(3,4-dimethoxyphenyl) ethoxy)-3-oxoprop-1-en-1-yl)-2-(3,4-dimethoxyphenyl)-7methoxy-2,3-dihydrobenzofuran-3-carboxylic acid (14) To a solution of 2 (0.068 mmol, 43 mg) in DCE (2 mL) was added Me3SnOH (0.34 mmol, 61 mg). The reaction mixture was stirred at 90  C for 20 h. After completion of reaction, 1 N HCl was added at 0  C. The mixture was extracted by DCM for three times. The organic layers were combined, dried over Na2SO4, filtered through a small pad of silica gel, and concentrated in vacuo. The resulting residue purified by silica gel column chromatography (hexanes:EtOAc:HOAc 1:1:0.005) to give diacid 14 as white solid (35 mg, 85%). 1H NMR (500 MHz, CD3COCD3) d 7.84 (d, J ¼ 16.0 Hz, 1H), 7.38 (d, J ¼ 8.6, 1H), 7.07 (d, J ¼ 1.9 Hz, 1H), 7.03 (d, J ¼ 8.6 Hz, 1H), 6.98e6.91 (m, 3H), 6.89e6.82 (m, 2H), 6.42 (d, J ¼ 16 Hz, 1H), 6.06 (d, J ¼ 5.1 Hz, 1H), 5.25 (dd, J ¼ 8.5, 4.2 Hz, 1H), 4.58 (d, J ¼ 5.1 Hz, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.74 (s, 3H), 3.19 (dd, J ¼ 14.3, 4.2 Hz, 1H), 3.09 (dd, J ¼ 14.3, 8.5 Hz, 1H). 13C NMR (126 MHz, CD3COCD3) d 172.97, 171.16, 166.49, 150.57, 150.11, 149.49, 149.35, 147.40, 143.07, 133.92, 130.00, 126.99, 125.30, 122.56, 121.39, 118.83, 117.27, 114.31, 114.26, 112.71, 112.65, 110.59, 88.18, 73.75, 60.54, 56.50, 56.42, 56.11, 56.00, 37.62. HRMS-ESI (m/z): calcd for C32H32NaO12 [M þ Na]þ 631.1786, found 631.1781. [a]23 D ¼ þ170.2 (c 0.51, CH2Cl2). 4.9. Lithospermic acid (1) 14 (0.049 mmol, 30 mg) and trimethylsilylquinolinium iodide (50 equiv, 806 mg) was added into a seal tube. The reaction mixture was stirred at 130  C for 3 h. The reaction was cooled to room temperature, and 1 N HCl was added slowly. The mixture was extracted by EtOAc for four times. The combined organic layers were dried by Na2SO4, filtered and concentrated under vacuum. The resulting residue was subjected to HPLC separation (YMC C18 column, MeCN:H2O:TFA 10:90:0.1 to 50:50:0.1 over 60 min at 1 mL/ min, detection: UV at 254 nm). The collected fractions were concentrated under reduced pressure to give 1 as yellow powder (5.8 mg, 22%). 1H NMR (500 MHz, CD3COCD3) d 7.85 (d, J ¼ 16.0 Hz, 1H), 7.30 (d, J ¼ 8.5 Hz, 1H), 6.89 (d, J ¼ 8.5 Hz, 1H), 6.88 (m, 1H), 6.86 (d, J ¼ 1.7 Hz, 1H), 6.82 (d, J ¼ 8.1 Hz, 1H), 6.80 (dd, J ¼ 8.2, 1.8 Hz, 1H), 6.73 (d, J ¼ 8.0 Hz, 1H), 6.67 (dd, J ¼ 8.0, 1.9 Hz, 1H), 6.38 (d, J ¼ 15.9 Hz, 1H), 5.98 (d, J ¼ 4.7 Hz, 1H), 5.18 (dd, J ¼ 8.6, 4.0 Hz, 1H), 4.53 (d, J ¼ 4.7 Hz, 1H), 3.10 (dd, J ¼ 14.4, 4.0 Hz, 1 H), 3.01 (dd, J ¼ 14.3, 8.6 Hz, 1H). 13C NMR (126 MHz, MeOD) d 175.07, 173.43, 168.10, 148.81, 146.62, 146.06, 145.25, 144.08, 133.74, 129.18, 127.59, 124.56, 121.95, 121.66, 118.24, 117.57, 116.36, 116.31, 113.38, 88.74,

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74.70, 57.48, 37.89. HRMS-ESI (m/z): calcd for C27H22NaO12 [M þ Na]þ 561.1003, found 561.1005. [a]23 D ¼ þ71 (c 0.16, MeOH), lit. 23 [a]23 D ¼ þ68.3 (c 0.8, CD3OD) [6], [a]D ¼ þ75 (c 0.2, MeOH) [8]. Melting point: 180e182  C. Acknowledgements We are grateful to the National Natural Science Foundation of China (No. 81602995) for financial support. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.tet.2018.08.028. References [1] G. Johnson, S.G. Sunderwirth, H. Gibian, A.W. Coulter, F.X. Gassner, Phytochemistry 2 (1963) 145. [2] (a) C.J. Kelley, J.R. Mahajan, L.C. Brooks, L.A. Neubert, W.R. Breneman, M. Carmack, J. Org. Chem. 40 (1975) 1804; (b) H. Wagner, D. Wittman, W. Schaffer, Tetrahedron Lett. 16 (1975) 547. [3] (a) T.O. Cheng, Int. J. Cardiol. 121 (2007) 9; (b) R.-W. Jiang, K.-M. Lau, P.-M. Hon, T.C.W. Mak, K.-S. Woo, K.-P. Fung, Curr. Med. Chem. 12 (2005) 237; (c) L. Zhou, Z. Zuo, M.S.S. Chow, J. Clin. Pharmacol. 45 (2005) 1345; (d) Y. Lu, L.Y. Foo, Phytochemistry 59 (2002) 117. [4] I.S. Abd-Elazem, H.S. Chen, R.B. Bates, R.C.C. Huang, Antivir. Res. 55 (2002) 91. [5] S.J. O'Malley, K.L. Tan, A. Watzke, R.G. Bergman, J.A. Ellman, J. Am. Chem. Soc. 127 (2005) 13496. [6] D.-H. Wang, J.-Q. Yu, J. Am. Chem. Soc. 133 (2011) 5767. [7] J. Fisher, G.P. Savage, M.J. Coster, Org. Lett. 13 (2011) 3376. [8] A.K. Ghosh, X. Cheng, B. Zhou, Org. Lett. 14 (2012) 5046. [9] T.G. Varadaraju, J.R. Hwu, Org. Biomol. Chem. 10 (2012) 5456.

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